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Azamethiphos is used in the salmon industry to treat sea lice and is subsequently discharged into the sea, which may affect non-target species (NTS). A rise in seawater temperature could enhance the sensitivity of NTS. Thus, in the present investigation, the combined effects of azamethiphos (0 µg L-1, 15 µg L-1 and 100 µg L-1) and temperature (12 °C and 15 °C) was assessed over time (7 days) in the gonads and gills of the oyster Ostrea chilensis, assessing its oxidative damage (lipid peroxidation and protein carbonyls) and total antioxidant capacity. Our results indicated that in gonads and gills, lipid peroxidation levels increased over time during exposure to both pesticide concentrations. Protein carbonyl levels in gills increased significantly in all experimental treatments; however, in gonads, only pesticide concentration and exposure time effected a significant increase in protein damage. In both, gill and gonad temperature did not influence oxidative damage levels. Total antioxidant capacity in gonads was influenced only by temperature treatment, whereas in the gills, neither temperature nor azamethiphos concentration influenced defensive responses. In conclusion, our results indicated the time of pesticide exposure (both concentrations) had a greater influence than temperature on the cellular damage in this oyster.
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Huntington's disease (HD) is caused by an expanded CAG trinucleotide repeat in exon 1 of the huntingtin (HTT) gene. We report the design of a series of HTT pre-mRNA splicing modulators that lower huntingtin (HTT) protein, including the toxic mutant huntingtin (mHTT), by promoting insertion of a pseudoexon containing a premature termination codon at the exon 49-50 junction. The resulting transcript undergoes nonsense-mediated decay, leading to a reduction of HTT mRNA transcripts and protein levels. The starting benzamide core was modified to pyrazine amide and further optimized to give a potent, CNS-penetrant, and orally bioavailable HTT-splicing modulator 27. This compound reduced canonical splicing of the HTT RNA exon 49-50 and demonstrated significant HTT-lowering in both human HD stem cells and mouse BACHD models. Compound 27 is a structurally diverse HTT-splicing modulator that may help understand the mechanism of adverse effects such as peripheral neuropathy associated with branaplam.
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Older adult drinking poses a growing public health concern, especially given the ongoing aging of the United States population. As part of a larger lifespan developmental project contrasting predictors of drinking reductions across different periods of adulthood, we tested age differences in effects of health problems on drinking declines across young adulthood, midlife, and older adulthood. We predicted these effects to be developmentally specific to midlife and older adulthood. We also tested moderation by alcohol use disorder (AUD) symptomatology and by indices of sociodemographic disadvantage (sex and race/ethnicity). Analyses used data from the National Epidemiologic Survey on Alcohol and Related Conditions (NESARC), leveraging NESARC's vast age range (18-90 + ; N = 43,093) and two waves of longitudinal data. Multiple-group cross-lag models tested differences across age groups in cross-lag paths between health problems and alcohol consumption. As hypothesized, health problem effects on drinking reductions were developmentally specific to midlife and older adulthood. However, models testing moderation by AUD symptomatology showed that these adaptive effects of health problems on drinking reductions did not extend to those with one or more AUD symptoms. Little evidence was found for moderation by sex or race/ethnicity. Findings support the notion of health concerns as a pathway to drinking reduction that increases in importance across the adult lifespan. However, given the moderation by AUD symptoms, findings also highlight a need to understand barriers to health-related pathways to drinking reduction among relatively severe midlife and older adult drinkers. These findings hold implications for lifespan developmental tailoring of clinical, public health, and policy interventions.
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Trastornos Relacionados con Alcohol , Alcoholismo , Humanos , Estados Unidos/epidemiología , Anciano , Adulto Joven , Adulto , Longevidad , Consumo de Bebidas Alcohólicas/epidemiología , Alcoholismo/epidemiología , Trastornos Relacionados con Alcohol/diagnóstico , Trastornos Relacionados con Alcohol/epidemiología , Estudios LongitudinalesRESUMEN
The pesticide azamethiphos used by the salmon industry to treat sea lice, is applied as a bath and subsequently discharged into the sea. The effects of azamethiphos concentration (0, 15 and 100 µg L-1) on the physiology of the Chilean oyster (Ostrea chilensis) at two temperatures (12 and 15 °C) was examined. In all azamethiphos treatments, oysters kept at 15 °C had clearance rates (CR) higher than oysters kept at 12 °C. The oxygen consumption rate (OCR) increased at higher temperatures, except with 100 µg L-1 of azamethiphos, where no changes were observed. Sixty days after the exposure, survival rates of 91 and 79% (15 and 100 µg L-1, respectively), were observed compared to the controls, a situation independent of the experimental temperature. The interaction between temperature and pesticide has detrimental effects on the physiological performance and survival of O. chilensis, and these effects should also be assessed for other non-target species.
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Ostrea , Plaguicidas , Animales , Plaguicidas/toxicidad , Temperatura , Organotiofosfatos/toxicidadRESUMEN
The disposal of antibiotics in the aquatic environment favors the selection of bacteria exhibiting antibiotic resistance mechanisms. Quinolones are bactericidal antimicrobials extensively used in both human and animal medicine. Some of the quinolone-resistance mechanisms are encoded by different bacterial genes, whereas others are the result of mutations in the enzymes on which those antibiotics act. The worldwide occurrence of quinolone resistance genes in aquatic environments has been widely reported, particularly in areas impacted by urban discharges. The most commonly reported quinolone resistance gene, qnr, encodes for the Qnr proteins that protect DNA gyrase and topoisomerase IV from quinolone activity. It is important to note that low-level resistance usually constitutes the first step in the development of high-level resistance, because bacteria carrying these genes have an adaptive advantage compared to the highly susceptible bacterial population in environments with low concentrations of this antimicrobial group. In addition, these genes can act additively with chromosomal mutations in the sequences of the target proteins of quinolones leading to high-level quinolone resistance. The occurrence of qnr genes in aquatic environments is most probably caused by the release of bacteria carrying these genes through anthropogenic pollution and maintained by the selective activity of antimicrobial residues discharged into these environments. This increase in the levels of quinolone resistance has consequences both in clinical settings and the wider aquatic environment, where there is an increased exposure risk to the general population, representing a significant threat to the efficacy of quinolone-based human and animal therapies. In this review the potential role of aquatic environments as reservoirs of the qnr genes, their activity in reducing the susceptibility to various quinolones, and the possible ways these genes contribute to the acquisition and spread of high-level resistance to quinolones will be discussed.
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While prior literature has largely focused on marriage effects during young adulthood, it is less clear whether these effects are as strong in middle adulthood. Thus, we investigated age differences in marriage effects on problem-drinking reduction. We employed parallel analyses with two independent samples (analytic-sample Ns of 577 and 441, respectively). Both are high-risk samples by design, with about 50% of participants having a parent with lifetime alcohol use disorder. Both samples have been assessed longitudinally from early young adulthood to the mid-to-late 30s. Separate parallel analyses with these two samples allowed evaluation of the reproducibility of results. Growth models of problem drinking tested marriage as a time-varying predictor and thereby assessed age differences in marriage effects. For both samples, results consistently showed marriage effects to be strongest in early young adulthood and to decrease somewhat monotonically thereafter with age, reaching very small (and nonsignificant) magnitudes by the 30s. Results may reflect that role transitions like marriage have more impact on problem drinking in earlier versus later adulthood, thereby highlighting the importance of life span developmental research for understanding problem-drinking desistance. Our findings can inform intervention strategies aimed at reducing problem drinking by jumpstarting or amplifying natural processes of adult role adaptation.
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The Rho kinase (ROCK) pathway is implicated in the pathogenesis of several conditions, including neurological diseases. In Huntington's disease (HD), ROCK is implicated in mutant huntingtin (HTT) aggregation and neurotoxicity, and members of the ROCK pathway are increased in HD mouse models and patients. To validate this mode of action as a potential treatment for HD, we sought a potent, selective, central nervous system (CNS)-penetrant ROCK inhibitor. Identifying a compound that could be dosed orally in mice with selectivity against other AGC kinases, including protein kinase G (PKG), whose inhibition could potentially activate the ROCK pathway, was paramount for the program. We describe the optimization of published ligands to identify a novel series of ROCK inhibitors based on a piperazine core. Morphing of the early series developed in-house by scaffold hopping enabled the identification of a compound exhibiting high potency and desired selectivity and demonstrating a robust pharmacodynamic (PD) effect by the inhibition of ROCK-mediated substrate (MYPT1) phosphorylation after oral dosing.
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Enfermedad de Huntington , Animales , Encéfalo/metabolismo , Modelos Animales de Enfermedad , Proteína Huntingtina/metabolismo , Enfermedad de Huntington/tratamiento farmacológico , Ratones , Inhibidores de Proteínas Quinasas/metabolismo , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/uso terapéutico , Quinasas Asociadas a rhoRESUMEN
The expanded polyglutamine-containing mutant huntingtin (mHTT) protein is implicated in neuronal degeneration of medium spiny neurons in Huntington's disease (HD) for which multiple therapeutic approaches are currently being evaluated to eliminate or reduce mHTT. Development of effective and orthogonal biomarkers will ensure accurate assessment of the safety and efficacy of pharmacologic interventions. We have identified and optimized a class of ligands that bind to oligomerized/aggregated mHTT, which is a hallmark in the HD postmortem brain. These ligands are potentially useful imaging biomarkers for HD therapeutic development in both preclinical and clinical settings. We describe here the optimization of the benzo[4,5]imidazo[1,2-a]pyrimidine series that show selective binding to mHTT aggregates over Aß- and/or tau-aggregates associated with Alzheimer's disease pathology. Compound [11C]-2 was selected as a clinical candidate based on its high free fraction in the brain, specific binding in the HD mouse model, and rapid brain uptake/washout in nonhuman primate positron emission tomography imaging studies.
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Encéfalo/diagnóstico por imagen , Compuestos Heterocíclicos con 3 Anillos/química , Proteína Huntingtina/metabolismo , Agregado de Proteínas/fisiología , Piridinas/química , Radiofármacos/química , Enfermedad de Alzheimer , Animales , Biomarcadores/metabolismo , Encéfalo/metabolismo , Radioisótopos de Carbono/química , Femenino , Compuestos Heterocíclicos con 3 Anillos/síntesis química , Compuestos Heterocíclicos con 3 Anillos/farmacocinética , Humanos , Macaca fascicularis , Masculino , Ratones Endogámicos C57BL , Estructura Molecular , Tomografía de Emisión de Positrones , Piridinas/síntesis química , Piridinas/farmacocinética , Radiofármacos/síntesis química , Radiofármacos/farmacocinética , Ratas Sprague-Dawley , Relación Estructura-ActividadRESUMEN
OBJECTIVE: Recent studies have examined the extent to which alcohol dependence (AD) criteria prospectively predict the course of AD. Critically, these studies have lacked a developmental perspective. However, the differential performance of criteria by age might indicate overendorsement in younger individuals. The current study examined AD criteria in terms of persistence and prediction of AD course and alcohol use by age in order to identify criteria that are likely to be overly endorsed by younger individuals. METHOD: The current study used longitudinal data from the National Epidemiologic Survey on Alcohol and Related Conditions to depict age differences in rates of new onset, recurrence, and persistence for each AD criterion, thereby showing how these three factors contribute to the overall age-prevalence curve of each criterion. Additionally, we tested age moderation of the predictive association between each criterion at baseline and new onset, recurrence, and persistence of syndromal AD. RESULTS: Some criteria (particularly, persistent desire or unsuccessful efforts to cut down or control drinking, and drinking despite physical/psychological problems) are both less persistent and less predictive of AD course among younger adults compared to older adults. CONCLUSIONS: These findings raise the possibility of elevated rates of false-positive AD among younger adults and suggest ways to improve the assessment of AD criteria. (PsycInfo Database Record (c) 2021 APA, all rights reserved).
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Consumo de Bebidas Alcohólicas/psicología , Alcoholismo/psicología , Etanol/efectos adversos , Adolescente , Adulto , Factores de Edad , Alcoholismo/diagnóstico , Femenino , Humanos , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Prevalencia , Pronóstico , Recurrencia , Adulto JovenRESUMEN
Background: Pharmacological approaches are widely used for post-traumatic stress disorder (PTSD) despite uncertainty over efficacy. Objectives: To determine the efficacy of all pharmacological approaches, including monotherapy, augmentation and head-to-head approaches (drug versus drug, drug versus psychotherapy), in reducing PTSD symptom severity. Method: A systematic review and meta-analysis of randomised controlled trials were undertaken; 115 studies were included. Results: Selective serotonin reuptake inhibitors (SSRIs) were found to be statistically superior to placebo in reduction of PTSD symptoms but the effect size was small (standardised mean difference -0.28, 95% CI -0.39 to -0.17). For individual monotherapy agents compared to placebo in two or more studies, we found small statistically significant evidence for the antidepressants fluoxetine, paroxetine, sertraline, venlafaxine and the antipsychotic quetiapine. For pharmacological augmentation, we found small statistically significant evidence for prazosin and risperidone. Conclusions: Some medications have a small positive effect on reducing PTSD symptom severity and can be considered as potential monotherapy treatments; these include fluoxetine, paroxetine, sertraline, venlafaxine and quetiapine. Two medications, prazosin and risperidone, also have a small positive effect when used to augment pharmacological monotherapy. There was no evidence of superiority for one intervention over another in the small number of head-to-head comparison studies.
Antecedentes: Los abordajes farmacológicos se usan ampliamente para el trastorno de estrés postraumático (TEPT) a pesar de su eficacia incierta.Objetivos: Determinar la eficacia de todos los abordajes farmacológicos, incluyendo monoterapia, potenciación y abordajes comparativos (droga versus droga, droga versus psicoterapia), en la reducción de la severidad de los síntomas de TEPT.Método: Se llevó a cabo una revisión sistemática y metanálisis de estudios controlados aleatorizados; se incluyeron 115 estudios.Resultados: Se encontró que los inhibidores selectivos de la recaptación de serotonina (ISRSs) fueron estadísticamente superiores a placebo en la reducción de los síntomas de TEPT, pero el tamaño de efecto fue pequeño (diferencia media estandarizada −0.28, IC 95% −0.39 a −0.17). Para agentes en monoterapia individuales comparados con placebo en dos o más estudios, encontramos para los antidepresivos fluoxetina, paroxetina, sertralina, venlafaxina y el antipsicótico quetiapina una evidencia estadísticamente significativa pequeña. Para la potenciación farmacológica, encontramos para prazosina y risperidona, evidencia estadísticamente significativa pequeña.Conclusiones: Algunos medicamentos tienen un efecto positivo pequeño en la reducción de la severidad de los síntomas de TEPT y pueden ser considerados como potenciales tratamientos en monoterapia; estos incluyen fluoxetina, paroxetina, sertralina, venlafaxina y quetiapina. Dos medicamentos, prazosina y risperidona, también tienen un efecto positivo pequeño cuando se usan para potenciar la monoterapia farmacológica. En el pequeño número de estudios comparativos, no hubo evidencia de superioridad para una intervención sobre otra.
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Antagonistas de Receptores Adrenérgicos alfa 1/farmacología , Antipsicóticos/farmacología , Inhibidores Selectivos de la Recaptación de Serotonina/farmacología , Trastornos por Estrés Postraumático/tratamiento farmacológico , Sinergismo Farmacológico , Quimioterapia Combinada , HumanosRESUMEN
The conceptualization of stress-responsive physiological systems as operating in an integrated manner is evident in several theoretical models of cross-system functioning. However, limited empirical research has modeled the complexity of multisystem activity. Moreover few studies have explored developmentally regulated changes in multisystem activity during early childhood when plasticity is particularly pronounced. The current study used latent profile analysis (LPA) to evaluate multisystem activity during fall and spring of children's transition to kindergarten in three biological systems: the parasympathetic nervous system (PNS), sympathetic nervous system (SNS), and hypothalamic pituitary adrenal (HPA) axis. Latent transition analysis (LTA) was then used to examine the stability of profile classification across time. Across both timepoints, three distinct profiles of multisystem activity emerged. One profile was characterized by heightened HPA axis activity (HPA Axis Responders), a second profile was characterized by moderate, typically adaptive patterns across the PNS, SNS, and HPA axis (Active Copers/Mobilizers), and a third profile was characterized by heightened baseline activity, particularly in the PNS and SNS (Anticipatory Arousal/ANS Responders). LTA of fall-to-spring profile classifications indicated higher probabilities that children remained in the same profile over time compared to probabilities of profile changes, suggesting stability in certain patterns of cross-system responsivity. Patterns of profile stability and change were associated with socioemotional outcomes at the end of the school year. Findings highlight the utility of LPA and LTA to detect meaningful patterns of complex multisystem physiological activity across three systems and their associations with early adjustment during an important developmental transition.
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Sistema Hipotálamo-Hipofisario , Sistema Hipófiso-Suprarrenal , Niño , Preescolar , Humanos , Hidrocortisona , Estrés PsicológicoRESUMEN
BACKGROUND: Due to the importance of both prostaglandins (PGs) and leukotrienes (LTs) as pro-inflammatory mediators, and the potential for eicosanoid shunting in the presence of pathway target inhibitors, we have investigated an approach to inhibiting the formation of both PGs and LTs as part of a multi-targeted drug discovery effort. METHODS: We generated ligand-protein X-ray crystal structures of known inhibitors of microsomal prostaglandin E2 synthase-1 (mPGES-1) and the 5-Lipoxygenase Activating Protein (FLAP), with their respective proteins, to understand the overlapping pharmacophores. We subsequently used molecular modeling and structure-based drug design (SBDD) to identify hybrid structures intended to inhibit both targets. RESULTS: This work enabled the preparation of compounds 4 and 5, which showed potent in vitro inhibition of both targets. SIGNIFICANCE: Our findings enhance the structural understanding of mPGES-1 and FLAP's unique ligand binding pockets and should accelerate the discovery of additional dual inhibitors for these two important integral membrane protein drug targets.
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Inhibidores de Proteína Activante de 5-Lipoxigenasa/farmacología , Descubrimiento de Drogas , Eicosanoides/antagonistas & inhibidores , Inhibidores Enzimáticos/farmacología , Prostaglandina-E Sintasas/antagonistas & inhibidores , Inhibidores de Proteína Activante de 5-Lipoxigenasa/química , Proteínas Activadoras de la 5-Lipooxigenasa/metabolismo , Eicosanoides/metabolismo , Inhibidores Enzimáticos/química , Humanos , Modelos Moleculares , Prostaglandina-E Sintasas/metabolismo , Relación Estructura-ActividadRESUMEN
BRAF is among the most frequently mutated oncogenes in human cancers. Multiple small molecule BRAF kinase inhibitors have been approved for treating melanoma carrying BRAF-V600 mutations. However, the benefits of BRAF kinase inhibitors are generally short-lived. Small molecule-mediated targeted protein degradation has recently emerged as a novel pharmaceutical strategy to remove disease proteins through hijacking the cellular ubiquitin proteasome system (UPS). In this study, we developed thalidomide-based heterobifunctional compounds that induced selective degradation of BRAF-V600E, but not the wild-type BRAF. Downregulation of BRAF-V600E suppressed the MEK/ERK kinase cascade in melanoma cells and impaired cell growth in culture. Abolishing the interaction between degraders and cereblon or blocking the UPS significantly impaired the activities of these degraders, validating a mechanistic role of UPS in mediating targeted degradation of BRAF-V600E. These findings highlight a new approach to modulate the functions of oncogenic BRAF mutants and provide a framework to treat BRAF-dependent human cancers.
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Descubrimiento de Drogas/métodos , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/metabolismo , Proteolisis/efectos de los fármacos , Proteínas Proto-Oncogénicas B-raf/metabolismo , Supervivencia Celular/efectos de los fármacos , Supervivencia Celular/fisiología , Relación Dosis-Respuesta a Droga , Humanos , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Proto-Oncogénicas B-raf/antagonistas & inhibidores , Vemurafenib/química , Vemurafenib/metabolismo , Vemurafenib/farmacologíaRESUMEN
This article presents an overview of the Louisiana Community Oil Spill Survey (COSS), the dataset used in "Community Sentiment following the Deepwater Horizon Oil Spill Disaster: A Test of Time, Systemic Community, and Corrosive Community Models" [1] as well as elsewhere [2-6]. The COSS, administered by the Louisiana State University's Public Policy Research Laboratory, consists of five waves of cross-sectional trend data attuned to the characteristics and effects of the 2010 BP Deepwater Horizon (BP-DH) oil spill on those coastal Louisiana residents most affected by the disaster. Respondents were randomly drawn from a list of nearly 6,000 households in the coastal Louisiana zip codes located in Lafourche Parish, Plaquemines Parish, Terrebonne Parish, and the community of Grand Isle. COSS data were initially collected in June 2010 when oil was still flowing from the wellhead, with additional data waves, collected in October 2010, April 2011, April 2012, and April 2013. The respective response rates were: June 2010, 20%; October 2010, 24%; April 2011, 25%; April 2012, 20%; and April 2013, 19%.
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BACKGROUND: Prior research on alcohol consumption and pain has yielded inconsistent results regarding the directionality of effects for both consumption-to-pain and pain-to-consumption relations. The present study sought to examine directionality of these relations by testing bidirectional longitudinal associations between consumption and pain interference, a crucial aspect of pain that captures pain-related disability and has been regarded as a valuable measure of treatment outcome. In addition, this study explored possible moderation of these bidirectional longitudinal associations by gender and alcohol use disorder (AUD) symptomatology. METHODS: Analyses included 29,989 current/former drinkers who were interviewed at both waves (2001 and 2004) of the U.S. National Epidemiological Survey on Alcohol and Related Conditions (NESARC). Analyses used self-report data from both waves on past-year average daily volume of alcohol consumed and past-month pain interference (1 item from the Medical Outcomes Study 12-item Short-Form Health Survey [MOS-SF-12]). AUDADIS-IV data from Wave 1 were used to index baseline AUD symptomatology (i.e., symptom count). Cross-lagged panel modeling and multigroup analyses were employed. RESULTS: Regarding the consumption-to-pain-interference relation, in general, higher baseline alcohol consumption was associated with lower subsequent pain interference at follow-up. However, among men with higher AUD-symptom counts, the opposite pattern emerged, with higher baseline alcohol consumption being significantly related to higher subsequent pain interference at follow-up. Regarding the pain-interference-to-consumption relation, higher baseline pain interference was significantly associated with lower subsequent alcohol consumption at follow-up, and no moderating effects were observed. CONCLUSIONS: The distinctive patterns of the consumption-to-pain-interference relation observed among men with elevated AUD symptomatology suggest that this relation might be driven by different mechanisms across different groups of individuals. Specifically, the detrimental effect of alcohol on pain interference might emerge at relatively advanced stages of AUD among men, consistent with Koob's Dark Side of Alcohol Addiction theory in human research.
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Consumo de Bebidas Alcohólicas/epidemiología , Alcoholismo/epidemiología , Alcoholismo/fisiopatología , Dolor/epidemiología , Factores Sexuales , Adulto , Consumo de Bebidas Alcohólicas/fisiopatología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Dolor/fisiopatologíaRESUMEN
OBJECTIVE: The aim of this study was to (1) assess the long-term mental and behavioral health outcomes of the Deepwater Horizon Oil Spill of residents in the Gulf Coast and to (2) identify populations that may be particularly vulnerable to future disasters. METHODS: The Survey of Trauma, Resilience, and Opportunity in Neighborhoods in the Gulf (STRONG) is a population-representative sample of 2520 coastal residents surveyed in Texas, Louisiana, Alabama, Mississippi, and Florida in 2016. We present prevalence estimates for positive screens of depression, anxiety, and alcohol misuse, as well as receipt of health care services. We examine differences in these outcomes across states, affected occupational groups, and demographic groups. RESULTS: Resource loss attributed to the spill was associated with positive screens for depression and anxiety. Almost 50% of adults screened positive for depression, anxiety, or alcohol misuse, but less than 20% of these currently access mental health care. Black residents were less likely to have health insurance and a usual source of care but were more likely to have visited the emergency room in the past 12 months. CONCLUSIONS: Surveillance data from STRONG can help policy-makers and other stakeholders develop targeted approaches to foster resilience, particularly among vulnerable populations, and thereby mitigate the effects of future disasters.
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Recursos en Salud/estadística & datos numéricos , Trastornos Mentales/etiología , Contaminación por Petróleo/efectos adversos , Adolescente , Adulto , Anciano , Alabama/epidemiología , Ansiedad/epidemiología , Ansiedad/etiología , Ansiedad/psicología , Depresión/epidemiología , Depresión/etiología , Depresión/psicología , Femenino , Florida/epidemiología , Golfo de México/epidemiología , Recursos en Salud/provisión & distribución , Estado de Salud , Humanos , Louisiana/epidemiología , Masculino , Trastornos Mentales/epidemiología , Trastornos Mentales/psicología , Persona de Mediana Edad , Mississippi/epidemiología , Contaminación por Petróleo/estadística & datos numéricos , Vigilancia de la Población/métodos , Encuestas y Cuestionarios , Texas/epidemiología , TiempoRESUMEN
Pim kinases are a family of constitutively active serine/threonine kinases that are partially redundant and regulate multiple pathways important for cell growth and survival. In human disease, high expression of the three Pim isoforms has been implicated in the progression of hematopoietic and solid tumor cancers, which suggests that Pim kinase inhibitors could provide patients with therapeutic benefit. Herein, we describe the structure-guided optimization of a series of quinazolinone-pyrrolodihydropyrrolone analogs leading to the identification of potent pan-Pim inhibitor 28 with improved potency, solubility, and drug-like properties. Compound 28 demonstrated on-target Pim activity in an in vivo pharmacodynamic assay with significant inhibition of BAD phosphorylation in KMS-12-BM multiple myeloma tumors for 16 h postdose. In a 2-week mouse xenograft model, daily dosing of compound 28 resulted in 33% tumor regression at 100 mg/kg.
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Antineoplásicos/uso terapéutico , Neoplasias Hematológicas/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/uso terapéutico , Proteínas Proto-Oncogénicas c-pim-1/antagonistas & inhibidores , Pirroles/uso terapéutico , Quinazolinonas/uso terapéutico , Animales , Antineoplásicos/síntesis química , Antineoplásicos/farmacocinética , Femenino , Humanos , Ratones SCID , Estructura Molecular , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/farmacocinética , Pirroles/síntesis química , Pirroles/farmacocinética , Quinazolinonas/síntesis química , Quinazolinonas/farmacocinética , Relación Estructura-Actividad , Porcinos , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
This article reviews literature aiming to explain the widespread reductions in binge and problem drinking that begin around the transition to young adulthood (i.e., "maturing out"). Whereas most existing literature on maturing out emphasizes contextual effects of transitions into adult roles and responsibilities, this article also reviews recent work demonstrating further effects of young adult personality maturation. As possible mechanisms of naturally occurring desistance, these processes could inform both public health and clinical interventions aimed at spurring similar types of drinking-related behavior change. This article also draws attention to evidence that the normative trend of age-related reductions in problem drinking extends well beyond young adulthood. Specific factors that may be particularly relevant to problem drinking desistance in these later periods are considered within a broader life span developmental framework.
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Alcoholismo/fisiopatología , Consumo Excesivo de Bebidas Alcohólicas/fisiopatología , Desarrollo Humano/fisiología , Desarrollo de la Personalidad , Adolescente , Adulto , Anciano , Alcoholismo/epidemiología , Consumo Excesivo de Bebidas Alcohólicas/epidemiología , Humanos , Persona de Mediana Edad , Adulto JovenRESUMEN
AICARFT is a folate dependent catalytic site within the ATIC gene, part of the purine biosynthetic pathway, a pathway frequently upregulated in cancers. LSN3213128 is a potent (16 nM) anti-folate inhibitor of AICARFT and selective relative to TS, SHMT1, MTHFD1, MTHFD2 and MTHFD2L. Increases in ZMP, accompanied by activation of AMPK and cell growth inhibition, were observed with treatment of LY3213128. These effects on ZMP and proliferation were dependent on folate levels. In human breast MDA-MB-231met2 and lung NCI-H460 cell lines, growth inhibition was rescued by hypoxanthine, but not in the A9 murine cell line which is deficient in purine salvage. In athymic nude mice, LSN3213128 robustly elevates ZMP in MDA-MB-231met2, NCI-H460 and A9 tumors in a time and dose dependent manner. Significant tumor growth inhibition in human breast MDA-MB231met2 and lung NCI-H460 xenografts and in the syngeneic A9 tumor model were observed with oral administration of LSN3213128. Strikingly, AMPK appeared activated within the tumors and did not change even at high levels of intratumoral ZMP after weeks of dosing. These results support the evaluation of LSN3213128 as an antineoplastic agent.